Gene therapy for the treatment of X-linked retinitis pigmentosa

Retinitis pigmentosa (RP) is an inherited degenerative disease causing severe retinal dystrophy and visual impairment mainly with onset in infancy or adolescence. Targeted next-generation sequencing (NGS) has become an efficient tool to encounter the enormous genetic heterogeneity of diverse retinal dystrophies, including RP. To identify disease-causing mutations in unselected, consecutive RP patients, we conducted Sanger sequencing of genes commonly involved in the suspected genetic RP subtype, followed by targeted large-panel NGS if no mutation was identified, or NGS as primary analysis. A high (70%) detection rate of disease-causing mutations was achieved in a large cohort of 116 unrelated patients. About half (48%) of the solved RP cases were explained by mutations in four genes: RPGR, EYS, PRPF31 and USH2A. Overall, 110 different mutations distributed across 30 different genes were detected, and 46 of these mutations were novel. A molecular diagnosis was achieved in the majority (82–100%) of patients if the family history was suggestive for a particular mode of inheritance, but only in 60% in cases of sporadic RP. The diagnostic potential of extensive molecular analysis in a routine setting is also illustrated by the identification of unexpected genotype-phenotype correlations for RP patients with mutations in CRX, CEP290, RPGRIP1, MFSD8. Furthermore, we identified numerous mutations in autosomal dominant (PRPF31, PRPH2, CRX) and X-linked (RPGR) RP genes in patients with sporadic RP. Variants in RP2 and RPGR were also found in female RP patients with apparently sporadic or dominant disease. In summary, this study demonstrates that massively parallel sequencing of all known retinal dystrophy genes is a valuable diagnostic approach for RP patients.

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“…With novel upcoming therapeutic options such as gene therapy, the identification of the disease-causing mutations has gained importance. [3]…”

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa

et al. 2018

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“…In conclusion, we present a small selection of females with a very severe phenotype that does not differ from the typical male pattern. In our opinion, gene therapy surgery should be warranted in this scenario [22]. Ophthalmologists and genetic counsellors should also be aware that women may show a male phenotype.…”

Section: Discussionmentioning

confidence: 99%

<b><i>RPGR</i></b>-Related X-Linked Retinitis Pigmentosa Carriers with a Severe “Male Pattern”

2020

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Background: X-linked retinitis pigmentosa (XLRP) due to mutations in the RPGR gene is a very severe form of RP, resulting in rapid disease progression and retinal dysfunction. Female carriers do not usually report symptoms. However, it has reported that carriers of XLRP can have a significant visual and retinal impairment. Objectives: To report a detailed description of 3 cases of severely affected females who presented with a “male” phenotype and have posed challenges at diagnosis, due to the apparent autosomal dominant family history. Method: Autofluorescence imaging (AF), colour imaging and optical coherence tomography (OCT) were performed. Confirmation of the genetic mutation was obtained by Sanger genetic sequencing. In 1 patient an X-inactivation analysis was performed to detect the X-inactivation ratio, as the percentage of cells tested in which each allele is active. Results: All the patients started suffering from night blindness in early childhood. Colour, fundus AF and OCT images showed the typical pattern of degeneration reported in men. One patient underwent retina implant surgery due to the severe atrophy. Conclusions: This is a small selection of females with a severe phenotype that do not differ from the typical male phenotype. In our opinion gene therapy surgery should be warranted in this scenario.

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“…Although not yet fully elucidated, it is thought that the photoreceptor degeneration observed in patients with XLRP caused by a mutation in RPGR is a result of defective protein trafficking in the connecting cilia (41). A majority of XLRP-causing mutations in RPGR have been located in the open reading frame 15 (ORF15) exon (38), an alternative splice product that is highly expressed in the retina (42). …”

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

“…Posttranslational glutamylation is known to be critical for the function of RPGR in photoreceptors; a lack of glutamylation in mice results in a phenotype similar to that observed in RPGR knockout mice (51). In an attempt to overcome these challenges and improve sequence stability, the coding sequence of RPGR ORF15 Has been optimized (42,50). In the case of gene therapy with AAV vectors, sequence optimization can provide increased transgene expression that limits the need for regulatory elements such as woodchuck hepatitis virus posttranscriptional regulatory element (WPRE), which use up limited AAV packaging capacity (42).…”

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

“…Two other studies have been initiated to assess retinal gene therapy for the treatment of XLRP. The first is an open-label phase 1/2 dose escalation study to evaluate the efficacy and safety of AAV2/5.hRKp.RPGR over 18 months in adults and children aged over 5 years with XLRP (NCT03252847; sponsored by MeiraGTx UK Ltd) (27,42). The second is also an open-label phase 1/2 dose escalation study over 36 months, which aims to assess the efficacy and safety of rAAV2tYF-GRK1-RPGR in adults and children aged over 6 years with XLRP (NCT03316560; sponsored by Applied Genetic Technologies Corp.) (28,42).…”

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

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Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

et al. 2019

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Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.

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Gene therapy for the treatment of X-linked retinitis pigmentosa

Cited by 40 publications

References 75 publications

Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa

Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa

<b><i>RPGR</i></b>-Related X-Linked Retinitis Pigmentosa Carriers with a Severe “Male Pattern”

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

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